Oral spiramycin formulations and method for preparing same

ABSTRACT

Formulations of spiramycin granules may be conducted by preparing a solution of albumin in the presence of an antifoaming agent, separately preparing a suspension of spiramycin in the presence of an antifoaming agent, granulating and drying a mixture of one or more sugars and water, mixing the albumin solution and spiramycin suspension with heating to coagulate the albumin, evaporating the solvents to obtain spiramycin granules, and mixing the sugar granules and spiramycin granules. Oral spiramycin formulations prepared according to this method are also disclosed.

The present invention relates to a new method for preparingmicroencapsulated spiramycin granules as well as to the formulationsobtained from these granules.

Spiramycin, as well as its salts and its esters, is an antibiotic with abroad activity spectrum whose use by the oral route especially inchildren is limited because of problems of taste. Indeed, spiramycin,its salts or its esters, has physical or chemical properties whichcause, at the level of the taste buds, a bitterness which results in aproblem of ingestion which may lead to the rejection of the medicinalproduct by vomiting phenomena.

In adults, it has been possible to circumvent these disadvantages byadministering spiramycin in the form of a tablet coated with a polymeror a glaze which avoids all contact between the active ingredient andthe taste buds. In young children, this solution cannot be envisaged.The pharmaceutical industry has long been searching for a liquid formwhich can be administered to children or to adults, which permits acorrect masking of the bitterness of the active ingredient even insolution.

The preparation of microcapsules of spiramycin coated with a protein,the latter being preferably albumin, is known via the SpanishCertificate of Importation No. 550171/7. It is specified in this textthat the microcapsules can be used for the preparation of liquidsuspensions. The method for preparing the said microcapsules is not easyto implement, it consists in preparing a mixture of spiramycin andalbumin, in coagulating the albumin with heat, then in washing the solidobtained several times, in centrifuging it and then in drying it. It isspecified in the text that the microcapsules have an irregular shape.

The present invention has made it possible to prepare ready-for-usegranules composed of spiramycin encapsulated in albumin and diluted witha mixture of sugars and aromatic substances. The mode of preparation isgreatly facilitated compared with the method described in the Spanishcertificate mentioned above. Indeed, it no longer requires intermediatestages for washing the microcapsules in order to remove the solvent andmakes it possible, in addition, to carry out all the stages in the sameapparatus until the final formulation is obtained.

This method for preparing ready-for-use spiramycin formulationsconsists:

in a first stage, in preparing a solution of albumin in a phosphatebuffer at pH 7.5 to 8.5 in the presence of an antifoaming agent;

in a second stage, in preparing a suspension of spiramycin in isooctanein the presence of an antifoaming agent;

in a third stage, in preparing a mixture containing sugars and water, ingranulating it and drying it by stirring under vacuum;

in a fourth stage, in mixing, in a turbosphere, the solution andsuspension of stages 1 and 2 based on an albumin over spiramycin weightratio of between 0.3 and 0.5, in heating the mixture to a temperature ofbetween 35° and 40° C. in order to emulsify it, and then in heating itto a higher temperature in order to coagulate the albumin;

in a fifth stage, in evaporating, under vacuum, the solvents of thepreceding mixture at a temperature of less than 65° C., under a pressureof less than 100 torrs;

in a sixth stage, in mixing the granules obtained in the third stage andin the fifth stage, based on a weight ratio of between five to one andfifty to one, optionally adding aromatic substances, sweeteners and/orcolourings.

According to one embodiment of the invention, during the first stage, anaqueous solution, buffered to pH 7.5-8.5 by mixing disodium andmonopotassium phosphate, is prepared in particular. The antifoamingagent which is added to this solution may be of chemical or physicalorigin. The physical agent may be a vacuum, the chemical agent may bechosen from anionic, cationic or nonionic surface-active agents (fattyacid esters and/or ethers). The use of sorbitan oleate is preferred.According to a preferred embodiment of the invention, about 0.3% byweight of sorbitan trioleate is added as antifoaming agent to thebuffered aqueous solution and finally albumin is added based on a weightratio relative to the buffered aqueous solution of about 20%. Thestirring is maintained for a few hours until the albumin dissolvescompletely.

According to an improved embodiment of the invention, the pH ispreferably adjusted to between 7.9 and 8.1 and the temperature ismaintained between 25° and 35° C.

According to one embodiment of the second stage of the invention, thespiramycin is dispersed in the turbosphere in a mixture of isooctane andantifoaming agent, preferably containing about 3.5% by weight ofsorbitan trioleate relative to the isooctane, the weight ratio betweenthe spiramycin and the isooctane/sorbitan trioleate mixture beingbetween 50 and 100%. According to an improved embodiment of theinvention, the use of a weight ratio of 80% is preferred.

According to one embodiment of the third stage of the invention whichmay equally well be a first stage or a fifth stage of the methodaccording to the invention or not exist if the sugar granule isavailable, a granule of sugars, for example a mixture of lactose andfructose and water is prepared, granulated and dried. This granulationmay be carried out in the turbosphere or in any other mixer/dryer,preferably before encapsulation of the spiramycin so as not to have toempty the turbosphere during manufacture. This granule is preferablyscreened in order to retain a particle size of less than 0.4 mm.

According to one embodiment of the fourth stage of the invention, thesolution of albumin in the buffer is introduced into the turbospherecontaining the spiramycin dispersed in isooctane. A quantity of albuminsolution is preferably introduced such that the weight ratio of albuminto spiramycin is between 0.3 and 0.5. This introduction is carried outmost preferably by increasing the turbosphere stirring speed to theregion of 70 to 90 revolutions per minute, the temperature being fixedespecially between 35° and 45° C. This stirring makes it possible toobtain a stable emulsion. To avoid destroying the protein duringcoagulation, the stirring is advantageously reduced to 10 to 30revolutions per minute while maintaining the temperature below 65° C.

According to the fifth stage of the method of the invention, thesolvents of the preceding mixture, that is to say water and isooctane,are evaporated under vacuum at a temperature of between 50° and 65° C.The stirring is slowed down, preferably to about 5 to 10 revolutions perminute and the vacuum is applied slowly up to a value of less than 100torrs and preferably up to a value of between 10 and 40 torrs, thetemperature being, for its part, preferably maintained below 60° C. Theencapsulated spiramycin obtained is screened so as to retain only theparticle size below 0.3 mm.

According to the sixth stage of the method according to the invention,the microcapsule granules obtained in the preceding stage are mixed withthe granules, consisting of sugar, obtained in the third stage or inanother stage of the method, and the aromatic substances, the sweetenersand the colourings are added. According to a preferred mixture, thesugar granules are added to the granules of microencapsulated spiramycinbased on a weight ratio of five to one to fifty to one.

The oral formulations, based on spiramycin encapsulated with albumin,which can be used and which are obtained by the method of the invention,preferably contain doses of between 150,000 to 3,000,000 internationalunits of spiramycin, and still more preferably, they contain 250,000international units of spiramycin per gram of mixture. They aretasteless and can therefore be easily ingested both by children and byadults.

The present invention will be more completely described with the aid ofthe following example which should not be considered as limiting theinvention.

EXAMPLE a) Preparation of the Buffer

107.17 kg of demineralised water (which corresponds to an excess of 40%of [sic] to subsequent losses), 0.938 kg of anhydrous disodium sodiumphosphate and 0,053 kg of monopotassium phosphate are mixed. Afterstirring for five minutes, a sample is taken in order to measure the pHwhich must be in the range 7.9-8.1. If the pH is too high, potassiumphosphate is added, if it is too low, sodium phosphate is added.

b) Addition of Albumin

There are added into the preceding solution 0.407 kg of sorbitantrioleate as antifoam and 27.04 kg of egg albumin, avoiding theformation of lumps. The mixture is stirred for three hours until totaldissolution is obtained. At the end of this time, the mixture isfiltered on a 0.2-mm filter in order to remove the foam formed.

c) Encapsulation

A Moritz TSI--500 Pharma turbosphere, heated by means of the jacket to atemperature of 40° C., is used. 44,572 kg of spiramycin are addedfollowed by a charge of 75 liters of isooctane. The paddles of theturbosphere are set into operation at a speed of 20 revolutions perminute. 1,937 kg of sorbitan trioleate are then charged, dissolved in6.84 liters of isooctane. The suspension is homogenised at 40revolutions per minute for 10 minutes.

The stirring speed is increased to 70-90 revolutions per minute and96.863 kg of the albumin solution are added thereto. The duration of theaddition is 10 to 20 minutes and the temperature of the solution is 35°to 42° C. The emulsion is then homogenised for another 5 to 10 minutes.The stirring is stopped and the appearance of a stable emulsion with ayellow-white colour is observed.

To coagulate the albumin, the temperature of the jacket is increased upto 80°-85° C. and the stirring speed is again increased up to 20 to 30revolutions per minute. When the first coagulation of the mass begins ataround 50°-53° C., the stirring is reduced to 15-20 revolutions perminute in order to avoid too much extrusion of isooctane from the mass.As the coagulation of the albumin progresses towards 56°-59° C., thestirring is again reduced down to 10-15 revolutions per minute in orderto avoid as much as possible the extrusion of isooctane from themicrocapsules. When the whole has become coagulated at around 61° C. thetemperature of the jacket is reduced so as to modify the temperature ofthe medium as slowly as possible.

d) Drying

When the temperature of the medium reaches 65° C. the vacuum is appliedand the stirring is reduced to 5 to 10 revolutions per minute. Theheating is reduced slowly, taking care to ensure that the innertemperature does not exceed 65° C. The speed of application of thevacuum is established as slowly as possible and the rate of evaporationof the mass which is most easily controlled corresponds to an innertemperature of 50° C. At this moment, the vacuum can be increased tounder 100 torrs and even up to 10 to 40 torrs. When the product issufficiently dry, it is discharged and it is screened on a 0.3-mmscreen.

e) Basic Granules

66.822 kg of lactose and 100.233 kg of fructose are introduced into theturbosphere after screening on a 0.4-mm screen. The stirring is carriedout at 20 revolutions per minute for 30 minutes. 2.406 liters of waterare added and the mixture is kneaded. The turbosphere is heated to70°-75° C. and the vacuum is applied. Within two to four hours, agranule having a diameter of less than 0.4 mm is obtained.

f) Final Mixture

0.134 kg of colouring, 16.706 kg of microencapsulated spiramycin (25% ofthe production), 3.341 kg of powdered raspberry flavouring, 3.341 kg ofbanana flavouring and 2,673 kg of aspartame are added to the sugargranules previously prepared. After 45 to 60 minutes, completehomogeneity is obtained. The powder obtained is passed over a screenwith a mesh size of less than 0.4 mm and distributed into suitablepackagings.

We claim:
 1. A method for preparing formulations of spiramycin granules comprising the steps of:in a first stage, preparing a solution of albumin in a phosphate buffer at pH 7.5 to 8.5 in the presence of an antifoaming agent; in a second stage, preparing a suspension of spiramycin in isooctane in the presence of an antifoaming agent; in a third stage, preparing a mixture containing one or more sugars and water and granulating and drying by stirring under vacuum; in a fourth stage, mixing the solution of the first stage and the suspension of the second stage in a turbosphere based on an albumin over spiramycin weight ratio of between 0.3 and 0.5 and heating the mixture to a temperature of between 35° C. and 40° C. in order to emulsify it and heating the mixture to a higher temperature in order to coagulate the albumin; in a fifth stage, evaporating the solvents of the preceding mixture at a temperature of between 50° C. and 65° C. under pressure of less than 100 Torr to obtain spiramycin granules; and in a sixth stage, mixing the granules obtained in the third stage and in the fifth stage based on a weight ratio of between 5:1 and 50:1.
 2. Method according to claim 1, wherein the antifoaming agent is either a vacuum or a surface-active agent.
 3. Method according to claim 1, wherein in the first stage, a solution of albumin containing about 20% by weight of albumin and about 0.3% by weight of sorbitan oleate is prepared.
 4. Method according to claim 1, wherein in the second stage, a suspension containing 50 to 100 g of spiramycin per 100 g of isooctane and about 0.3% of sorbitan oleate is prepared.
 5. Method according to claim 1, wherein in the third stage, granules having a particle size of less than 0.4 mm are prepared.
 6. Method according to claim 1, wherein in the fourth stage, during the coagulation of the albumin, the emulsion is heated to a temperature of less than 65° C.
 7. Method according to claim 1, wherein in the fifth stage, the solvents are evaporated under a pressure of between 10 and 40 torrs.
 8. A method according to claim 1, further comprising, following the fifth stage, removing granules having a particle size of more than 0.3 mm.
 9. An oral pharmaceutical composition comprising a spiramycin compound, encapsulated in albumin prepared according to the method of claim
 1. 10. The oral pharmaceutical formulation of claim 9 further comprising sugar, aromatic substances and a sweetener and wherein the formulation contains a dose of 25,000 international units of spiramycin per gram of mixture. 